Steroidal lactones and their preparation



United States Patent 3,355,461 STERGIDAL LACTGNES AND THEHR PREPARATION ABSTRACT OF THE DISLOURE This invention relatesto new steroids of the 17-oxa-D- homo-A -pregnene-3,16,2O-trione and 17-oXa-D-h0mo-A- n0r-A -p1'egnene-2,16,2O-tri0ne series, which may contain additional double-bonds in the 1,2 and/or 6,7-positions, halogen or lower alkyl substituents in the 9st or IZzx-POSitions, a fi-hydroxy or oxo group in the ll-position, a lower alkyl or halogen substituent in the 6-position, and a halogen, hydroxy or acyloxy substituent in the 21position. These compounds are physiologically active substances that possess progestational activity, if unsubstituted in the C-ring, and glucocorticoid activity if they contain an 11 8- hydroxy or ll-keta group. The compounds are prepared from the corresponding A -pregnene-17a-ol-3,16,20-trione or A-nor-A -pregnene-17a-ol-2,16,2O-trione by treating the latter with a strong base.

' This invention relates to new chemical compounds and more particularly to new steroids of the 17-oXa-D-homo- A -pregnene-3,16,2O-trione (including the pregnadiene and pregnatriene) and 17-0Xa-D-h0mo-A-n0r-A -pregnene-2, 16,20-trione series.

Although the invention includes all steroids of the 17- oxa-D-homo-M-pregnene-S,16,20-trione and 17-0xa-D- homo-A-nor-M-pregnene-Z,16,20-trione series, the particularly preferred compounds are those of the formula (IIHzZ X 0 0 R i l A l I wherein Y is methylene (CH ethylene or vinylene (CH=CH); the 6,7-p0siti0n is either saturated or double-bonded; A is hydrogen or methyl; R is hydrogen, R is hydrogen or hydroxy, or together R and R is oxo (=0); each X is hydrogen, halogen (preferably chloro or fluor-o), or lower alkyl, at least one X being hydrogen or lower alkyl; X is hydrogen, lower alkyl, or halogen (preferably chloro or fiuoro), in either the alpha or beta position; and Z is hydrogen, halogen, hydroxy, or acyloxy, the acyloxy group preferably being that of a hydrocarbon carboxylic acid of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic and propionic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic acid),

the monocyclic ar(lower alkanoic acids) (e.g., phenacetic and fi-phenylpropionic acid), the cycloalkanecarboxylic acids, and the cycloalkenecarboxylic acids.

The new steroids of this invention are physiologically active substances. Those unsubstituted in the C-ring possess progestational activity and hence may be used in lieu of and in the same manner as progesterone in treatment of conditions for which progesterone is used. Those containing an llfl-hydroxy or ll-keto group possess glucocorticoid activity and hence may be used in lieu of and in the same manner as hydrocortisone in the treatment of conditions for which hydrocortisone is used.

The new steroids of this invention are prepared by reacting a corresponding steroid of the A -pregnene-17uol-3,16,20-trione or A-nor-M-pregnene-l7u-ol-2,16,20- trione series with a strong base, such as an alkali metal hydroxide (e.g., sodium hydroxide) or metal alkoxide (e.g., potassium t-butoxide or sodium methoxide) in a suitable solvent such as water, methanol, ethanol and other alcohols, dioxane, dimethylformamide or combinations of these solvents.

Suitable starting steroids can be prepared as disclosed in US. patent application, Ser. No. 443,080, filed Mar. 26, 1965, now matured to Patent No. 3,316,156, and include 1 7ec-hydroxy-1 6-ketoprogesterone, 17a-hydroxy-16-keto-A-norprogesterone,

1 7 a-hydroxy- 1 6-ketol-dehydroproge sterone,

1 'fu-hydroxy-l 6-keto-6 -dehydro pro gesterone, t-i1ydf0Xy-1 6-keto- 1 ,6-tetrad ehydroprogesterone, 17a-hydroxy-16-keto-1 l-desoxycorticosterone and 21-esters thereof,

6a-rnetl1yl- 1 7a-1'1YdIOXY-1 6-ketoprogesterone,

6 B- chlorol7u-hydroxy- 1 6 -ket-o pro gesterone, 6a-fluoro-17u-hydroxy-16-ketoprogesterone, 9e-halo-l 1B,17a-dihydroXy-16-ketoprogesterones (such as 9a-fluoro-11,8,17u-dihydroxy46-ketoprogesterone),

9a-ha1o- 17 a-hydroxy-l 1,16-diket0progesterones,

9a-halo-115,17a-di-hydroxy-16-keto-1- dehydroprogesterones,

9u-halo-l 1B,17a-dihydroXy-16-keto-6- dehydroprogesterones,

61,9 u-dihalo-l 1/3-17a-dihydroxy-16-ketoprogesterones,

9a-halo-1fi-keto-hydrocortisones and 21-esters thereof (such as 9a-fluoro-16-ketohydrocortisone and its 2l-acetate), 9a-halo-16-keto-prednisolones and 2l-esters thereof (such as 9a-fluoro-16-ketoprednisolone and its ZI-acetate), 9a-halo-16-keto-6-dehydrocortisones and 21-esters thereof,

9 a,21-dihalo-11/3,17a-dihydroxy-16-ketoprogesterones,

9 a,2l-dihalo-11/3,17u-dihydroXy-16-keto-1- dehydroprogesterones,

9a,21-dihalo-11/3,17a-dihydroxy-16-keto-6- dehydroprogesterones,

9a-halo-1 1B,17m-dihydroXy-16-keto-A-norprogesterones,

17a-hydroXy-16-keto-19-norprogesterone,

17ix-hydroxy-16-keto-l9-norcorticosterone,

6a-halo-16-keto-hydrocortisones and their 21-esters, 6m-halo-16-keto-prednisolones and their 21-esters, 6m,9 x-dihalo-16-keto-hydrocortisones and their 21-esters, 6a,9x-dihalo-16-keto-prednisolones and their 21-esters, 16-ketohydrocortisone and its 2l-esters, and 16-ketoprednisolone and its 21-esters.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 1 7aB-acelyl-1 7-oxa-D-h0m0-andr0st-4-ene-3 ,1 6-di0ne 4 1 3 105 (chloroform), kmax. 232 my (5, 17,200), mg? 5.74, 5.87, 5.95 (sh), 6.17 7 393 1 4.24 5., 3

H), 5.74 (d., J=1 e.p.s., 17aoeH), 7.71 (s., 21-011 8.83 (5., 19CH 9.00 5., 18CH Similarly, by following the procedure of Example 1,

but substituting the indicated substituted l6-keto-17a-hydroxy-progesterone for the 16-keto-l7a-hydroxyprogesterone in the example, the indicated substituted 17aB-acetyl- 17-oxa-D-homo-androst-4-ene-3,16-dione is obtained.

Example Substituted 16-ket0-17a-liydi'oxyprogesterone Substituted lo-keto-lr'afl-acetyl-U-oxa-D- Reactaut homo-audrost-at-eue-3, lfi-dione Product l-dehydro l-dehydro. 6-dehydro fi-dehydro. 1 G-tetradehydro. LS-tetradehydro. 21-hydroxy ll-hydroxy. (Ea-methyl Got-methyl. fid-chloro 6B'chloro. 6a-fluo1o fia-fluoro. 9i1-fiuoro-11fl-hydroxy Qwflu rO-HB-hydmXy. 9a-fiuoro-11-keto Qa-fiuoro-ll-keto.

9a,21-difluoro-11B-hydroxy-l-dehydro 19-nor and extracted with chloroform. The chloroform is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from acetone-hexane gives about 53 mg. of 17afi-acetyl- 17-oxa-D homo-androst-4-ene-3,16-dione having a melting point about 205-207", [0:1 :3 +3.6 (chloroform),

Similarly, by following the procedure of Example 2, but substituting the indicated substituted l6-keto-17a-hydroxy- A-norprogesterone for the 16-keto-l7a-hydroxy-A-norprogesterone in the example, the indicated substituted 17B- acetyl 17 oxa D homo A norandrost 3 ene- 2,16-dione is obtained:

Example Substituted 16-ketoalga-l?droxy-A-progosteroue ant liomo-A-noraudrost-3-ene-2, 16-dione Product 4.27 (s., 4-H), 5.75 (s., 172taH), 7.71 (5., 21

mg, 239 mu (6, 14,600),

Si(Me) DGOI;

CH 8.81 (s., 19CH 9.01 (5., 18CH Analysis.Calcd. for 0 11 0., (344.44 0, 73.22; H, 8.19. Found: 0, 73.22; H, 8.19.

EXAMPLE 2 1 7B-acetyl-1 7-0xd-D-h0m0-A-norandr0st-2-ene-2,16-di0ne Following the procedure of Example 1 but substituting 16-keto-l7a-hydroxy-A-norprogesterone for the l6-ket0- l7a-hydroxyprogesterone there are obtained about 39 mg. of 172.5 acetyl 17 oxa D homo A norandrost- 3-eue-2,16-dione having a melting point about 170172,

This invention may be variously otherwise embodied within the scope of the appended claims:

What is claimed is:

1. A compound selected from the group consisting of and the 6,7-dehydro derivatives thereof, wherein Y is selected from the group consisting of methylene, ethylene and vinylene; A is selected from the group consisting of hydrogen and methyl; R is hydrogen, R is selected from the group consisting of hydrogen and hydroxy, and together R and R is 0x0; each X is selected from the group consisting of hydrogen, chlorine, fluorine and lower alkyl, at least one X being selected from the group consisting of hydrogen and lower alkyl; X is selected from the group consisting of hydrogen, lower alkyl, chlorine and fluorine; and Z is selected from the group consisting of hydrogen, chlorine, fluorine, hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms.

2. 17a,3 acetyl 17 oxa D androst 4 ene 3,16- dione.

3. 17afi acetyl 17 oxa D homo A norandrost- 3-ene-2,16-dione.

4. A process for preparing a compound of claim 1,

which comprises interacting a compound selected from the group consisting of steroids of the formula CHzZ JAMES C. PATTEN, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,355,461 November 28, 1967 Patrick A. Diassi It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, line 52, for "-2-ene-", in italics, read -3-enein italics; column 4, line 2, for

maolj 1 Nujol Nux. read max. column 5, line 16, for "-Dandrost-" read D-homo-androstcolumn 6, line 17, for the claim reference numeral "2" read l Signed and sealed this 24th day of December 1968.

(SEAL) Attest:

Edward M. Fletcher, Jr. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE FORMULA 